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Histol Histopathol (2003) 18: 259-274

Histology and Histopathology
Cellular and Molecular Biology

Review Molecular pathogenesis of urothelial bladder cancer
D. Theodorescu
Department of Urology, University of Virginia, Charlottesville, Virginia, USA

Summary. Carcinoma of the urinary bladder is the second most common urologic malignancy. In addition, these tumors are one of the best understood genitourinary neoplasms with a well defined etiology, natural history, tumor biology, treatment options and outcome. This level of understanding arises as a consequence of multiple factors and represents a convergence of knowledge from diverse scientific disciplines. Insight provided by these disciplines, coupled with unique features of this neoplasm which make it assessable for detection, monitoring and treatment, combine to make this disease a model system for modern oncology. The intent of this review is to provide the reader an overview of our current understanding of this tumor from the standpoint of its molecular biology as related to tumor development and progression. Key words: Bladder cancer, Molecular pathogenesis,

Tumor Invasion
Molecular basis of tumor development

The first insight into the etiology of transitional cell carcinomas of the urinary bladder began with the observation of an increased incidence associated with industrial development. Workers in the aniline dye industry in Germany were noted to be at increased risk for the development of this tumor (Hunstein and Rehn, 1975). This association made bladder neoplasms the first of what would subsequently be recognized as many chemically induced tumors. Subsequent understanding has come to identify the process of uroepithelial transformation as one of contact carcinogenesis. Carcinogens ingested by one of multiple routes, either inhaled, consumed, or absorbed through the skin, are concentrated in the urine and subsequently come in contact with the lining of the urinary tract. This diffuse exposure predisposes to what has come to be known as field change. Thus the entire uroepithelium to which
Offprint requests to: Dr. Dan Theodorescu, University of Virginia, Department of Urology, P.O. Box 800422, Charlottesville, Virginia 22908, USA. e-mail:

urine has been exposed may have multiple areas of frank or preneoplastic transformation. Early clinical observations regarding the biology of the “at risk” field suggested that sites of preneoplastic changes could follow several distinct clinical courses. It is possible that areas of dysplasia remain simply dysplastic. Alternatively, the urinary epithelium can progress either to superficial bladder neoplasms, characterized by recurrence but rare life threatening progression, or along the path towards invasion with its well recognized risk of mortality. Evidence in support of these disparate pathways comes from the low progression rate of the majority of superficial bladder tumors, coupled with the fact that many invasive neoplasms present as such initially. An example of a clinical evidence based pathway detailing these distinctions in tumor biology is illustrated in figure 1 below (Droller, 1992). Insight afforded by these clinical observations has played a central role in generating hypotheses, developing models, and directing basic research in bladder cancer. Not only have these clinical observations served as the basis for research undertakings, but these subsequent research activities have in turn provided strong evidence to support the validity of these clinical models.

Models of molecular carcinogenesis must explain the relevant clinical natural history and aspects of tumor behavior such as uncontrolled cellular proliferation, neovascularization, and altered apoptosis. In addition, models of neoplastic transformation should account for other clinically relevant features of the neoplasm in question. For superficial and invasive transitional cell carcinomas of the urinary bladder, these would include tumor recurrence and tumor metastasis respectively. The historic view of two stage carcinogenesis in which tumor initiation (mutation) is followed by tumor promotion (epigenetic changes) has been conceptually important but is currently thought to be too simplistic. It is now believed that there may be six or more independent mutational events (Hay, 1991; Loeb, 1991; Reznikoff et al., 1996; Weinstein, 2000; Goel et al.,

and 4-aminobiphenyl. Endogenous mutagenic mechanisms such as DNA oxy-radical damage. In addition to these environmental exposures. a PAH. 177-92. Proposed pathway for bladder tumor development derived from clinical observation. Damage to DNA induced by these adducts is hypothesized to lead to mutations in proto oncogenes and/or tumor suppressor genes. 1996) or induce epigenetic effects (MacLeod. The property that is common to all of the diverse types of chemical carcinogens is that they can form directly or are metabolized to highly reactive electrophilic forms (Talalay. Together. Lutz. 1. 1991). 1990. Interestingly. In the late 19th century. There is considerable evidence to suggest that DNA is the molecular target of these agents. 2. The normal role of the host enzymes which act on chemical carcinogens is to convert these foreign Fig. Ames. chemical carcinogens may be genotoxic. Lutz. 1996) with dose response relations being linear or non-linear (Swenberg et al. non-genotoxic (Melnick et al. suggesting that these components may be direct mutagens contributing to the development of bladder cancer. and in individuals with abnormal detoxification mechanisms (B). Weinstein. 1990b). an arylamine. 1990a. 1989).260 Molecular pathogenesis of bladder cancer 2001) necessary for carcinogenesis. Fig. 1991. de-purination and polymerase infidelity also contribute to carcinogenesis (Breimer. these will highlight how the effect of a chemical carcinogen may be altered by the characteristics of the host and serve as both a model system and framework for further research in this area. 1995). benzopyrene.J. 1991. 1987. Semin Urol.. Two components of tobacco smoke. CYP1A2: hepatic cytochrome P450 1A2. 11. neither PAHs nor arylamines are direct carcinogens and therefore it would seem that additional steps are necessary for their activation and metabolism (Fig. 1990. 1991. Many different exposures and risk factors have been identified in bladder cancer. 2001. 1991) leading to a debate regarding the relative importance of endogenous versus exogenous mutagenic events and the value of animal bioassays or short term mutagenic assays for assessment of human cancer risks (Ames and Gold. 2a). GST-M1: glutathione S transferase M1. Infante. Weinstein.. tobacco smoking has also been associated with an elevated risk for multiple types of human cancers (Shopland et al. 2001). In the section below we will discuss two of the best characterized molecular paradigms leading to transitional cell carcinoma. Several of the chemicals identified in tobacco smoke have been shown to cause cancer in laboratory animals (Vineis and Caporaso. McCormick. the German physician Rehn observed an association between the occurrence of bladder cancer and exposure of workers to aromatic amines (arylamines) and polycyclic aromatic hydrocarbons (PAH) compounds found in the dyestuff industry.. Hay. with divergence early in the process of tumorigenesis. Note that the superficial and invasive pathways are distinct. NAT 2: Nacetyltransferase 2. (from Jones P. and Droller M. Pathways of development and progression in bladder cancer: new correlations between clinical observations and molecular mechanisms. These electron deficient species can attack the many electron rich or nucleophilic sites in molecules such as proteins and nucleic acids to form covalent adducts or induce mutagenesis (Wormhoudt et al.. Hypothetical model of carcinogen activation and detoxification and resulting cellular consequences in patients with normal detoxification (A) . Furthermore. 1991. 1999). .A. Loeb. form adducts with DNA. 1993).

the status of these enzymes may explain in part the wide variation in bladder cancer risk in different ethnic and racial groups (Foster. making some genetic sequences more at risk than others. an in vivo (Theodorescu et al. 1993)..261 Molecular pathogenesis of bladder cancer lipophilic compounds into more hydrophilic forms that can be readily excreted. Yu et al. NAT2 does not appear to play a role in bladder carcinogenesis induced by PAH (Hayes et al. The NAT2 enzyme is encoded by a single polymorphic gene (Garte et al. Dipple. these enzymes inadvertently form a reactive product. 1988). As expected from this chemistry. Two of the genes. HRAS and P53. 1998). this molecule stimulates the activation of other downstream mediators which are associated with enhanced cell motility and invasion (Gildea et al. 1995). by specific DNA repair processes and host cell type. In addition to NAT2. Two isoenzymes of N-acetyltransferase (NAT 1 and NAT 2) have been identified in humans (Wormhoudt et al.. 1993). 1991). However. Support for this idea comes from results demonstrating that transfection of an HRAS gene will convert SV40 immortalized human urothelial cells into invasive transitional cell carcinomas (Christian et al. Pratt et al. and each class of agents reacts selectively with purine and pyrimidine targets.. 1996).. Branch et al. alternative processing of arylamines can occur by detoxifying pathways (Fig. 2b). individuals who detoxify arylamines slowly due to decreased activity of these pathways. 1990. Due to its critical role. Recent reports (Czerniak et al.. 1993b)... In addition. 1990) has also been studied in relation to bladder cancer risk. 2a).. Risch et al. namely. the mutations found in activated RAS protooncogenes associated with tumors of animals exposed to N-nitroso compounds are predominantly . 1992). 1993. Several recent case control studies have investigated the relationship of NAT2 phenotype or genotype and bladder cancer risk (Hein. targeting of carcinogens to particular sites in DNA is determined by the nucleic acid sequence (Levy et al.. In addition. HRAS overexpression per se is not restricted to the malignant state in bladder tissue. 1999).. Hydroxylamines are then hydrolyzed in the acidic urinary environment allowing formation of adducts with nucleophilic sites in the transitional bladder mucosa. NAT2 and GST-M1 likely play key roles in the risk for bladder cancer development in individuals exposed to similar doses/durations of carcinogens. However. 1979. Detailed staining for HRAS in normal bladder tissue has revealed that the basal (progenitor) cells of the multilayered transitional epithelium stain with the highest intensity while more superficial (differentiated) compartments stain to a much lesser degree. 1990) study has implicated this molecule in several of the steps involved in tumor invasion. 1982) can occur and result in the induction of bladder cancer. 1995)... the interaction with DNA is likely not to be random. (Essigmann and Wood. On the other hand. with individuals having any two of several possible mutant alleles display a slow acetylator phenotype and hence exhibit impaired detoxification of carcinogenic arylamine (Bell et al.. able to cause base mispairing or small deletions. glutathione S transferase M1 (GST-M1). In the case of carcinogenic arylamines.. 1992). Branch et al.. the first step in this process is N-oxidation catalyzed by hepatic cytochrome P450 1A2 isoenzyme (CYP1A2) (Butler et al. Thus... a small GTPase involved in signal transduction (Bos. leading to missense or nonsense mutations (Essigmann and Wood. A number of specific genes are known to be mutated by chemical carcinogens. 1995). 1990. have also been implicated in bladder tumorigenesis and progression. with the most studied of these pathways being N-acetylation. 1996) or expression of a mutant protein (Parada et al. which has resulted in significant individual and population variability when the activity of this enzyme is measured (Kalow and Tang... It is thus conceivable that a deregulation of HRAS gene expression (Fontana et al. 1989). For genotoxic carcinogens. These electrophilic metabolically active forms of arylamines or hydroxylamines can form adducts with hemoglobin or circulate freely as glucuronide conjugates and be excreted in the urine (Bryant et al.. in attempting to create a hydrophilic product. Metabolites of several PAH that are present in cigarette smoke as well as arylamines are known or potential substrates of GST-M1 (Board et al. but the spectra of mutations seems to be dependent on the agent... 2002).. supporting the notion that HRAS overexpression is causally related to tumor progression and not merely epiphenomenon. 2001). 1995. This enzyme has been shown to be inducible by several environmental factors including cigarette smoke. 1982). 1993).. 1992) utilizing PCR-based methods. The HRAS gene codes for p21Ras. Fortunately.. In addition. 1993a) (Fig. 1990. Case et al. 1994. have substantially higher risk of bladder cancer. which was the first proto oncogene found to be mutated in the T24 bladder cancer cell line (Parada et al. genotoxic carcinogens are potent mutagens. Thus the level of normal HRAS protein diminishes considerably with differentiation. it is not surprising to find indirect evidence that a phenotype associated with enhanced CYP1A2 activity. a family member of a class of enzymes which detoxify reactive chemicals by promoting their conjugation to glutathione (Board et al. For example. Bell et al. 1993b. revealed that approximately 40% of bladder tumors harbor HRAS codon 12 mutations. 1988. 1995) and have demonstrated that “slow aceltylators”. Most of these reactions are catalyzed by cytochrome P450 dependent mono oxygenases located predominantly in the liver. Both NAT2 and GST-MI have shown racial/ethnic variations which may explain in part why similar smoking habits result in different risks of bladder cancer (Bell et al. may be a risk factor for bladder cancer (Kaderlik and Kadlubar. In addition. Evidence from clinical studies using immunohistochemical techniques has demonstrated a correlation between the levels of the Ras protein and the degree of tumor invasiveness and that HRAS expression is an independent prognostic variable for tumor invasion(Fontana et al.

. 1993).. Mutations in P53 are particularly detrimental due to this gene’s multiple cellular regulatory and supervisory roles and Wouters. 1994.. Recent studies (Weinstein. Lu et al. such as tobacco-specific nitrosamines. 1993). 1994). a large number of reports have surveyed the cytogenetic changes found in TCC (Knowles et al. P53) into human cancer cells where the respective endogenous gene is inactive usually promotes marked inhibition of growth. environmental carcinogens can induce alterations of both gene types. Using cytogenetic. physiologically dependent on) the continued activity of specific activated or overexpressed oncogenes for maintenance of their malignant phenotype. 1996) changes may occur relatively early in the genesis of . then correction of just one mutation should have only a modest inhibitory effect. 1993b. These results are unexpected because. 2000). it would appear that chromosome 9 (Simoneau et al. Finally. and the striking therapeutic effects of the drug imatinib mesylate (STI571/Gleevec) that targets the Bcr-Abl oncogene in CML (Kantarjian et al. 2000). the antitumor effects of viral vectors encoding the p53 tumor suppressor gene (Kuball et al. Recent immunohistochemical studies of patients with bladder TCC have revealed a significant correlation between the number of cigarettes smoked and the incidence of positive P53 immunohistochemistry. the target gene and the tissue involved. Clinical evidence that oncogene addiction exists is provided by specific antibodies against the Her-2/neu receptor (Vogel et al. 1991) with up to 40% of bladder cancers harboring such lesions. these data are consistent with the notion that cancer cells are often "addicted to" (that is. Interestingly. 1994. adding another layer of complexity in humans. indicate that human exposure to mutagens may result in a narrow non-random spectrum of mutations (Greenblatt et al..262 Molecular pathogenesis of bladder cancer G:C→A:T base substitutions (Loechler et al. indicating that mutational spectra may be dependent on the causal agent. 2002) have shown that brief loss of oncogene (for example. 2002) and progression (Esrig et al. Thus. some cancer cells seem to be "hypersensitive" to the growthinhibitory effects of specific tumor suppressor genes (Weinstein. 1994). In this section we will highlight the genetic abnormalities associated with neoplastic transformation and focus on those associated with progression later on. Mutations are rare in lowgrade papillary tumors but are common in CIS and more invasive high-grade bladder cancers. 1994). 1993). An important question is whether genes that are crucial for the initial development of a specific tumor are required for maintaining the malignant phenotype of that tumor. the spectra of KRAS gene mutations in adenocarcinomas vary according to tissue sites.. recent results suggest that p53 might modulate the repair of DNA adducts generated from the human bladder carcinogen ABP in its target human uroepithelial cells. Reintroducing a wild-type tumor suppressor gene (for example. 2002. While smokers did not have a different mutational spectrum than non smokers. 2002). have yet other spectra (Ronai et al.. 1984). Studies of TCC revealed consistently high incidence of chromosomal abnormalities in chromosome 9 (Orlow et al... 2002) may be due to tumor suppressor hypersensitivity. 2002). These studies present an optimistic message with respect to new approaches for treating cancer. 1984). suggesting that P53 may play a role in both transformation (Simoneau and Jones. Especially valuable have been studies of the timing of occurrence of these mutations during different stages of bladder cancer pathogenesis. Spruck et al. if these cancer cells evolved simply through the stepwise acquisition of several mutations and altered gene expression. molecular genetic and immunohistochemical methods. 2002) that are being used to successfully treat breast cancer. Another important genetic target for chemical carcinogenesis is the P53 tumor suppressor... 1999).. Mutations in the P53 tumor suppressor gene are a frequent event in both transitional cell and squamous cell carcinomas of the bladder (Sidransky et al. As outlined above for Ras and P53. these experiments have revealed that the mutations detected in tumors occur overwhelmingly at only one of the possible mutation sites. which might contribute to increased genomic instability and neoplastic progression (Swaminathan et al. and other chemical classes. HRAS) overexpression caused the tumor cells to differentiate into normal cells. and/or inhibition of tumorigenesis in mice (Weinstein. Although there are several guanine residues in RAS codons that would generate a transforming protein if substituted by adenine. Rodriguez-Alonso et al. This gene is of particular relevance in bladder cancer because of its putative roles in both transformation (Simoneau and Jones.. In vitro studies using either prokaryotic or human cells. 1996) and P53 (Reznikoff et al. Currently. In addition. induction of apoptosis.. Lu et al. a general pattern seems to be emerging as to which genes and/or chromosomal locations are important for tumor development and progression. they did exhibit a higher frequency of double mutation events (Habuchi et al. 1994) and progression (Esrig et al. This implies that in p53 null cells the unrepaired DNA damage could cause accumulation of mutation.. produce a different mutation spectrum (Marshall et al. 2002).. Studies comparing cases of bladder cancer from smoking and non smoking patients showed an increased frequency of G:C→C:G transversions in both groups. Genetics of tumor development The molecular basis of urothelial transformation and progression can be deduced from numerous studies carried out over the last several years. 1994) and 17p (Dalbagni et al.. Taken together.. Likewise... and the inactivation of tumor suppressor genes. to these studies.. PAHs.. on the other hand. Multistage carcinogenesis is regarded as a consequence of the accumulation of somatic genetic alterations which include activation of cellular proto oncogenes.

1994). The importance of P53 in bladder tumorigenesis was suggested by the high frequency of LOH of chromosome 17p where this gene is located (17p13. indicate that replication errors have occurred (Peltomaki et al.. Finally. 1993). resulting in a selective growth advantage of cells harboring these defects. Chromosome 9 deletions are often found early in bladder tumor development. Among these are also p15 (INK4B/MTS2) which together with p16 can inhibit the phosphorylation of the retinoblastoma protein (RB). 1993). 1999). monitoring the fidelity of DNA synthesis and apoptosis (Choisy-Rossi et al. 1995). 1995) and kidney (Cairns et al. Shariat et al. A model has been recently proposed which hypothesizes two different pathways leading to the development of superficial bladder tumors including carcinoma in situ (Fig. microsatellite instability at loci on chromosome 9.. and Droller M. Proposed pathway for bladder tumor development derived from molecular epidemiological data.. Pathways of development and progression in bladder cancer: new correlations between clinical observations and molecular mechanisms. 1993). Linnenbach et al. 1994)..b) and E-Cadherin (Byrne et al. 1993).. 1993). 1990. genes such as MSH2 may themselves be targets of carcinogenic insults. 1994). thereby inhibiting the cell cycle.A.. 1995). 1993. the less the capacity of repair the greater the potential for the generation of heterogenous populations some of which exhibiting novel and more malignant attributes such as enhanced growth. a case study by Schoenberg et al. From Jones P. 2001) are associated with progression. CDKN2A encodes a protein which is part of a new group of cell cycle inhibitory molecules known as cyclin dependent protein kinases (CDK) (Serrano et al. p53 codes for a 53kDa phosphoprotein with DNA binding properties which is involved in multiple cell functions including gene transcription. 1996) examined case reports and epidemiological studies on TCC and concludes that there is evidence for a Fig. an area commonly altered in bladder cancer (Knowles et al. 11. In addition to these changes.20)(p15.1). which may have been an initiating factor in the disease. which are routinely used in the analysis of loss of heterozygosity (LOH) in human cancers. Korkolopoulou et al. 3). Recent genetic evidence has suggested that different clinical forms of TCC may result from different genetic lesions (Simoneau and Jones.q11). . While there is significant evidence to support the role of p53 in bladder tumor progression. growth factor independence and drug resistance among many others. 1993.263 Molecular pathogenesis of bladder cancer TCC while other changes such as EGFR (Theodorescu et al... the role of p53 has only recently been clarified in tumorigenesis of TCC. Semin. microsatellite instability has been linked to alterations in the MSH2 gene. occurring in up to 40% of cases (Gruis et al. A recent literature review by Kiemeney and Schoenberg (Kiemeney and Schoenberg. distinct pathways for superficial and invasive tumors parallels the model developed from observations of clinical biology (Fig. Urol. The role of p53 as a target for chemical carcinogenesis was discussed earlier. they may be reflecting severe deregulation of cellular DNA which if left unchecked may lead to unrepaired mutations in key regulatory genes such as p53. 2001. The patient was found to have the germline translocation t(5. In addition. Loss of either of these genes may have profound implications on the cell cycle and result in uncontrolled growth and tumor formation.. a finding also observed in other cancers such as lung (Merlo et al. ovary (Schultz et al.. 1998a. located on 2p16 (Leach et al. Recently.. Microsatellites are sequences of polymorphic nucleotide repeats found throughout the human genome (Weber. this gene has been implicated in both tumor formation and progression when accompanied by changes in p53 (Friedrich et al... This model postulates that chromosome 9 alterations in normal cells lead to papillary superficial TCC while P53 mutations lead to carcinoma in situ (CIS/Tis). which codes for an enzyme involved in DNA repair. 3. Since microsatellite abnormalities found in TCC appear to be early changes (Gonzalez-Zulueta et al. Both P53 and chromosome 9 losses can play a complimentary role further downstream in tumor progression in concert with other genetic changes. The persistence of these errors is an indication of the reduced ability of cancers to repair mutations. 2001). In colon cancer. In addition..... (1996) describes a patient who developed TCC of the bladder and renal pelvis at an early age. Kwiatkowski et al. p53 mutations may be induced by carcinogens as outlined above. was found in TCC (Gonzalez-Zulueta et al. The greater the instability. 2001. often accompanied by p15 loss is a very frequent occurrence in bladder cancer. 1). 177-92. 1992). 1994.. The loss of p16. Orlow et al. The divergent.. abnormalities or instabilities consisting of alterations of the number of repeats of a specific microsatellite in tumor DNA when compared to normal tissue DNA.J.. 1994). A candidate tumor suppressor gene CDKN2A :p16 was recently identified in the 9p21 region (Cairns et al.

See. Using a molecular analysis of Xchromosome inactivation in women with multifocal bladder tumors Sidransky et al provided strong evidence to suggest that the multifocal tumors were clonal in origin (Sidransky et al. Anecdotal evidence in support of this concept in addition to the unusual recurrence rate include the temporality of recurrence in relation to surgical removal of a primary lesions and the location of recurrences in relation to the index lesion. See et al. Its uniquely high metachronous recurrence rate. Zhang et al. 2001. 1980) and the specific mechanisms involved in tumor implantation delineated by See (See et al. Nonetheless some minor issues related to the precise mechanism of recurrence remain unresolved. 1975). frees tumor cells from their underlying site of origin and effectively disseminates them throughout the luminal surface of the bladder. Given the central role of cellular adherence to clots at the site of urothelial injury. They found identical microsatellite alterations on multiple chromosomes in 80% of patients with multifocal recurrences. that is electrosurgical disruption into a fluid-filled medium.. Subsequently. 1987). 2002. 1992. specificity compared to classical techniques (Seripa et al. Tsai found mosaicism in the human uroepithelium which suggested that clonal heterogeneity within the bladder was more limited than previously thought (Tsai et al. microsatellite alterations are common in bladder cancer and analysis of genomic instabilities in urine samples has been recently evaluated as a method for bladder cancer screening with promising results in terms of sensitivity. The concept of urothelial field change following exposure to a urinary carcinogen is both intuitively appealing and supported by multifocality and associated dysplasia in this disease (Hunstein and Rehn. Nonetheless other contact carcinogen induced tumors should have similar risks and yet fail to have metachronous recurrence rates approximating those associated with superficial bladder neoplasms. the local milieu must be conducive to the ultimate outgrowth of the adherent cell or cells. Importantly. 1993. 1989. While the etiologic debate regarding the mechanism of tumor recurrence has been largely resolved.. and Kaplan clearly demonstrated associated areas of dysplasia and preneoplasia in the urothelium intervening between sites of frank neoplasia. These tumor cells must remain viable in the detached state and subsequently be able to adhere to sites on the urothelial surface. Berger et al. and develop a vascular support structure. the molecular mechanisms underlying the ability of superficial bladder tumors to implant and grow at sites different from the primary are largely undefined.. In the 1950’s. Melicow. outlined the requisite steps necessary for tumor implantation and or intraepithelial tumor dissemination to occur (See and Chapman. Surgical injury associated with the process of electrosurgical resection of bladder tumors results in sites of urothelial injury which selectively predisposes to tumor cell adherence via the formation of fibrin clots and effective entrapment/adherence of tumor cells at these sites. 1995). For this reason. This would include an ability for the cells to divide. 1993a). several studies have suggested that tumor intrinsic pericellular proteolysis through one of several fibrinolytic pathways may be a regulator of tumor cell adherence and ultimate outgrowth (See and Williams. 1990).. See et . While a number of theories have been proposed to account for this unique feature of superficial bladder cancer. Clinical observation and basic science research has provided some insight into factors associated with certain of the aforementioned steps. The mechanism of bladder tumor ablation. has served as the basis for a longstanding debate in the urologic literature. The pendulum swung several times in the ensuing years. other authors have proposed intraepithelial tumor dissemination and or treatment induced implantation as a phenomenon accounting for the idiosyncrasy of superficial bladder cancer recurrence biology (Soloway and Masters. However subsequent work by McDonald showed that urothelial malignancies could be implanted into and grow on sites of urothelial trauma even given relatively crude immunosuppression and understanding of transplant rejection in that era. Indeed further evidence suggested that the bladder could develop from as few as 200 primordial cells and that the risk of tumor development and recurrence might be a consequence of limited diversity within the progenitor cell population. These observations were later expanded on by Soloway (Soloway and Masters..264 Molecular pathogenesis of bladder cancer familial bladder cancer gene.. Most recently this same group did microsatellite analysis on patients with multifocal metachronous tumor recurrence (Takahashi et al. Habuchi demonstrated that heterotopic urothelial recurrence was associated with identical mutations in P53 at both the upper and lower track sites of occurrence (Habuchi et al. 2002). Debate on this issue is traceable to the turn of the century when Albarran first proposed implantation as a mechanism accounting for bladder tumor recurrence.. Utting et al. 1998). 1980). Overall this combination of data provides virtually conclusive evidence that the majority of superficial bladder recurrences are clonal in their etiology. Following adherence.. distinguishing it from all other organ sites involved by contact carcinogenesis. In the case of implantation the obvious first step is the presence of free floating tumor cells on the luminal surface of the bladder. 1992). proliferate. A definitive answer to the issue of the mechanism of bladder tumor recurrence was not provided until early in the 1990’s.. which is a distinct entity from the known cancer predisposition syndromes. two fundamental theories have received greatest attention. 2001. Molecular basis of superficial tumor recurrence A central feature of the clinical biology of superficial bladder cancer is its idiosyncratic rate of recurrence. and given the unique nature of the lower urinary tract.

little work has been done to define whether specific molecular alterations in pericellular proteolysis might account for patterns of recurrence. Rosin et al. 1997). 1994) and associates screened 83 cases of transitional cell carcinoma for loss of heterozygosity (LOH) on all autosomal chromosome arms. Molecular basis of bladder cancer progression current section we will highlight the cytogenetic. 1997). 1994).. 1999).. 2000). 1994). In this section we will focus and highlight the changes occurring when superficial bladder cancers become muscle invasive. and 17p (Reznikoff et al. Tumors labeled as “invasive” on the other hand are those penetrating the true muscle of the bladder wall. However.. 1990) from early invasion of the basement membrane to widely metastatic disease. molecular genetic and immunohistochemical evidence supporting the role of specific genetic changes in the progression of bladder cancer to muscle invasive disease. 1998) found LOH with at least one allele lost on the long arm of chromosome 10 in 9/20 (45%) invasive transitional cell carcinomas.. While a number of associated factors have been identified. involving alterations at chromosomal locations 3p (Li et al. Some of these changes have also been observed in a recently characterized highly tumorigenic variant of the T24 human bladder cell line (Gildea et al. has important biologic functions. Historically however. 8p (23%). the incidence of LOH on this chromosome was found in 40% of tumors for at least one locus.. 1996). . However when cohorts with significant proportions of invasive tumors were investigated (Cappellen et al. CIS is more aggressive and behaves more akin to T1 than Ta tumors. (Crew et al. allowing for the establishment of a vascular support structure. LOH on chromosome 10 was observed mainly in muscleinvasive or high grade tumors. and is a mechanical barrier to tumor cell invasion. these studies are at a very preliminary stage.. and 13q (15%).. 1996). In general. Wick et al.. despite being truly superficial. Knowles (Knowles et al. Other facets of the implantation process. 1994). 1994. revealed loss of this chromosome in 67% of specimens from patients with histologically confirmed transitional cell carcinoma (Wheeless et al. 1995). the latter of which were most likely invasive or to have high chance of future progression to invasive disease. In these cases. The most frequent losses were monosomies of chromosome 9 (57%). 1997. 1996) cancer. Previous studies on predominantly superficial bladder cancer specimens (Knowles et al. 4q (Polascik et al. This series was composed of a majority of superficial low grade lesions and thus the incidence of the various losses would be reflective of the genetic alterations specifically present in this cohort of patients. cellular production of vascular endothelial growth factor. 1994) indicated an overall low frequency of chromosome 10 allele losses and deletions in bladder cancer. Remarkably. 15 (Wheeless et al. 4p (22%). Recently. have been alluded to in other work. Kagan et al. organs are composed of a series of tissue compartments separated from each other by two types of extracellular matrix: basement membranes and interstitial stroma (Bernstein and Liotta. thus not penetrating the basement membrane of the bladder wall.. Conversely.. 1998). urologists have also considered T1 tumors as superficial despite their invasion of the lamina propria.. Other groups have focused on identifying the common deletions specifically associated with tumor progression. 1996). As a group. losses on chromosomes 11p (32%).. LOH studies have also suggested that human chromosome 15 may harbor a novel putative tumor suppressor gene which appears to play a role during metastasis in breast and bladder (Wick et al. 1998).. tumor progression encompasses a spectrum of clinical and biological changes in both the tumor and the host (Mahadevan and Hart.... 17p (32%). This observation supported other studies where fluorescence in situ hybridization (FISH) for chromosome 15 specific centromeric repeat sequences. Subsequently. In a recent series. The epidermal growth factor/TGF alpha autocrine and paracrine loops have been suggested to predispose to recurrence (Turkeri et al.. The nuances of what is meant by invasive and superficial bladder cancer are worth mentioning here.. 18q (Brewster et al. 1995).. Due to the significant drop in a patients’ prognosis with any step in tumor progression.265 Molecular pathogenesis of bladder cancer al. the genetic basis of this phenomenon is therefore a subject of considerable clinical importance. 1995). since they are somewhat at odds with the pure definition of tumor invasion which is the penetration of normal tissue barriers such as the basement membrane. Confirming these findings. progression of superficial tumors to muscle invasion has profound consequences with respect to prognosis and treatment. In the purest sense only stage Ta and CIS tumors are truly “superficial”. Cytogenetic changes associated with TCC progression While less common than tumor recurrence. 10 (Cappellen et al. In the Several recent studies have examined the common regions of deletion in human bladder tumors (Knowles et al. Kagan and colleagues (Kagan et al. has been suggested as a prognostic feature correlating with recurrence risk. such as proliferation and neovascularization. most stage T1 lesions are more prone eventually to invade the detrusor during subsequent recurrences than are Ta tumors.. In fact.. 8p (Wagner et al. The extracellular matrix determines tissue architecture.. a somewhat different spectrum of abnormalities was observed. This may be the result of the differing genetic lesions that led to its formation compared to those leading to Ta/T1 cancers (Rosin et al. 1994). 1994. The precise mechanisms responsible for dysregulation of cellular expression of these various proteins remain to be clarified.

2001. 13 were categorized as RB altered.. with concentrations up to 10-fold greater per milliliter than those found in blood. despite a correlation with progression (Byrne et al. 2001) while those to survival were sometimes (Shimazui et al. 1991).. However. decreased E-cadherin expression correlated with both increased grade and stage of bladder cancer... with 26 of these 28 lesions being present in muscle-invasive tumors (Cairns et al. 1998b) studies that have implicated this molecule in several of the steps involved in tumor invasion. abnormal E-cadherin expression correlated with shorter patient survival (Bringuier et al.. 1994) in bladder tumors may be related to bladder tumor progression. patients with increased EGFR expression on their tumor cells did not survive as long as patients with normal EGFR expression. 1994).266 Molecular pathogenesis of bladder cancer Recently. no significant difference was found between patients with high levels of EGFR expression and those with low EGFR values(Nguyen et al. 1997)..1 and shown to behave like an invasion suppressor gene in vitro and in vivo in experimental systems (Mareel et al.. Similar to HRAS.. In addition. a Ca 2+ dependent cell adhesion molecule.. 2001. 1987).. More importantly. gene amplification and gene rearrangement does not appear to be a common mechanism for EGFR overexpression in bladder cancer (Sauter et al.. 1996) but not always (Lipponen and Eskelinen. 1994). Supporting the notion that EGFR overexpression is causally related to tumor progression and not merely an epiphenomenon are a number of in vitro (Theodorescu et al. this situation is likely to potentiate the consequences of EGFR overexpression since EGFR’s in bladder cancer are functional (Messing and Reznikoff. Below. such as cell motility. Loss of RB (Reznikoff et al.. located on chromosome 16q22. 1998. 1995). 1995) and higher rates of recurrence (Chow et al. superficial human bladder cancer cells which were engineered to overexpress either mutated or normal HRAS also begin overexpressing EGFR at both the mRNA and protein levels. Normal urothelium expresses E-cadherin. P53 (Lacombe et al.. 2001) and distant metastasis (Mialhe et al... we will discuss the evidence suggesting roles for these genes in bladder cancer progression. 1996) and ECadherin (Schmitz-Drager et al. these data suggest that regulation of EGFR is altered in bladder cancer. was observed in 14 patients. from undetectable RB levels to heterogeneous expression of RB.. RB alterations in bladder cancer as a function of stage was studied in 48 primary bladder tumors (Cordon-Cardo et al. 1994). 2002). has allowed us to focus on areas of the genome which are have both altered expression and chromosomal changes leading to the discovery of a new metastasis suppressor gene (see “Molecular and immunohistochemical changes associated with TCC progression” below). which accompanies cell dissociation and acquisition of motility. Shariat et al. including the RB locus on 13q14. our laboratory has developed a novel technique which combines information obtained from gene expression array analysis of human cancer cells with that of chromosomal position to allow expression mapping (Harding et al.. 1997). Several investigators further examined E-cadherin expression in bladder cancer samples and sought a correlation with tumor behavior. since EGF is present in large quantities in urine (Chow et al. Taken together. 1996... suggesting that EGFR overexpression might be associated with the phenotypic transition from superficial to invasive forms of disease. 1996) expression has also been related to this transition. E-cadherin (CDH1) The disruption of intercellular contacts. while only 1 of the 10 superficial carcinomas had the altered RB phenotype. were found 28 of 94 cases. However. This may explain the inverse relation between expression of Ecadherin and bladder tumor grade (Syrigos et al. 1994).. Shariat et al. In an early study on 49 patient specimens (24 superficial and 25 invasive tumors). 1991. stage (Gorgoulis et al. 1997) and progression in superficial forms of the disease (Lipponen and Eskelinen.. when the comparison of survival was limited to patients with invasive bladder cancer. Retinoblastoma (RB) Deletions of the long arm of chromosome 13. These relationships to stage and grade were subsequently confirmed by other groups (Griffiths et al. Shimazui et al. As such they may be causally related to the transition from superficial to invasive disease. Theodorescu et al. 1992) where a spectrum of altered patterns of expression. 1996). is correlated with a redistribution of E-cadherin over the entire cell surface and within the cytoplasm. 1996. This latter apparent inconsistency may be due to a lack of statistical power in the various analyses to demonstrate an effect. Molecular and immunohistochemical changes associated with TCC progression Epidermal growth factor receptor (EGFR) Studies utilizing immunohistochemical techniques (IHC) have suggested that overexpression of HRAS protein (discussed above) (Fontana et al.. Of the 38 patients diagnosed with muscle invasive tumors.. Byrne et al. 1995) shown. Comparing the results obtained with this technique to those of comparative genomic hybridization (CGH). Interestingly.. 1991).. EGFR expression levels in bladder cancer have been associated with increasing pathologic grade. 1996) and the epidermal growth factor receptor (EGFR) (Lipponen and Eskelinen. Patient survival was decreased in . 1993). Most importantly. therefore HRAS might also play a role in transcriptional regulation of EGFR besides its role in EGFR signal transduction (Bos.

77% in the non-expressors independent of stage and grade.. Cote et al. and DNA ploidy. 2000) have investigated the possibility that altered patterns of P53 expression correlated with tumor progression in patients with T1 bladder cancer. Another study (Lipponen.. 1998) however this is not found in all studies (Wada et al.5% for Group A. RB changes are associated with proliferative indices (Ioachim et al. Several groups (Lipponen. 1999. Other studies have attempted to clarify the role of P53 as a prognostic marker in muscle-invasive tumors.. However in this last study. Zlotta et al. 1998).. Sarkis et al. while P53 overexpression correlated only with grade. while 8 of 15 grade 3 bladder carcinomas were found to have intragenic mutations. Moch et al. 1994). In patients with transitional-cell carcinoma confined to the bladder.. 1993) reported an analysis of T1 tumors using immunohistochemistry and 20% positive nuclear staining as the cutoff value. this was driven by a marked difference in P53 expression between pTa (37% positive) and pT1 (71%) tumors. Thus patients with normal protein expression for both genes may be managed conservatively. mutations were not identified in any of the 10 grade 1 and 2 lesions. while there was no difference between pT1 and pT2-4 tumors. stages pTa to pT4 from 243 patients who were treated by radical cystectomy were examined for the IHC detection of P53 protein (Esrig et al. Disease specific survival was also associated with altered patterns of P53 expression. The long term survival in the P53 overexpressors was 41% vs. stage. homozygous deletions. A study focusing on the clinical progression of T1 tumors has demonstrated that patients with normal expression of both proteins have an excellent outcome. 1999. an accumulation of P53 in the tumor-cell nuclei predicted a significantly increased risk of recurrence and death. Progression and tumor grade were both significantly related to P53 nuclear overexpression. Structural alterations of the P53 gene were investigated using single strand conformation polymorphism (SSCP) in 25 bladder tumors and mutations in 6 of 12 invasive carcinomas were found. One out of 11 grade I (9%). 2000). 1993.. These data indicate the some clinical utility of stratification of T1 bladder cancer patients based on P53 and RB nuclear protein status. Pfister et al. 1993. (1993) studied the overexpression of P53 by IHC in 179 patients and found that P53 immunostaining to strongly correlate with tumor stage. Moreover. Another study (Matsuyama et al. and lymph-node status. 1992... IHC P53 protein expression analysis was performed in 90 patients with transitional cell carcinoma . Peyromaure et al.267 Molecular pathogenesis of bladder cancer RB altered patients compared with those with normal RB expression. IHC detectable P53 protein was studied in 42 bladder carcinomas. with patients in group 2 having significantly shorter progression free intervals. while only 1 of 13 superficial bladder tumors had such mutations (Fujimoto et al. 1997b. Jahnson and Karlsson. 1993). In another study (Soini et al.. In a third study... P53 was evaluated in 90 bladder tumors from 111 patients treated with neoadjuvant MVAC (Sarkis et al. Patients with T1 tumors were retrospectively stratified into two groups with either <20% tumor cells (group A) with positive nuclear staining or >20% of cells with nuclear immunoreactivity for P53 (group B) (Sarkis et al. 2002). Patients with abnormal expression of either or both proteins had a significant increase in progression (Grossman et al. There were significantly more P53 positive cases in stage T2T4 tumors than in stage T1 tumors. Two recent studies (Cordon-Cardo et al.. and structural rearrangements. In one study.. whereas patients with alterations in one and particularly both genes may require more aggressive treatment. 1997a). such as intragenic mutations. and there was no significant difference between grade 2 and grade 3 tumors.. histologic specimens of transitional-cell carcinoma of the bladder.5% per year for group B and 2. The imbalance produced by an enhanced proliferative activity and a decreased apoptotic rate may further enhance the aggressive clinical course of the bladder tumors harboring both P53 and RB alterations. The mean follow-up time was greater than 10 years. are frequent events in bladder cancer (Cordon-Cardo et al. 12/22 grade 2 (55%) and 8/9 grade 3 (89%) tumors showed positivity for P53. Nuclear P53 reactivity was then analyzed in relation to time to recurrence and overall survival. P53 Genetic alterations of the P53 gene. S-phase fraction. Ioachim et al. indicating perhaps that this gene may have its primary role in progression from superficial to muscle invasive disease rather than further downstream in the metastatic cascade. stage. 1993). P53 expression was not an independent predictor of disease progression. In addition.. In addition. 1995). a strong overall association between P53 expression and grade was driven by a marked difference between grade 1 (28%) and grade 2 tumors (71%).. 1994) analyzed 42 specimens of transitional cell carcinoma by interphase cytogenetics with a fluorescence in situ hybridization technique (FISH) and found that P53 deletion was significantly correlated with grade. 1992).. 2000). conflicting results have been obtained when RB status has been examined in patients with invasive tumors (Logothetis et al. Similarly. In another study. with no patient showing disease progression. There were significantly more P53 positive cases in grade 2-3 tumors than in grade 1 tumors. 1998) have also shown that RB and P53 alterations can further deregulate cell cycle control at the G1 checkpoint and produce tumor cells with reduced response to programmed cell death. Conversely. The relationship of P53 expression and BCG treatment response in patients with high risk superficial cancer has been evaluated but no clear concisus is yet apparent (Fontana et al. independently of tumor grade. Patients with P53 overexpression had a significantly higher proportion of cancer deaths.. Disease progression rates were 20. 1999a..

1998). 357369. Wiest J.A. human homolog of..S. 1999b). 1999b.. Natl. 1996. Bartsch G. 1995).A. 2002). Res. Amplification and protein overexpression of the ERBB2 gene located on 17q11. 475.. Genotype/phenotype discordance for human arylamine N-acetyltransferase (NAT2) reveals a new slow-acetylator allele common in African-Americans. However. Positive nuclear staining of tumor cells by the antibody to P53 protein was detected in 32 cases. Genetic heterogeneity of the human glutathione transferases: a complex of gene families. 85. Urol. most of which were invasive and nonpapillary tumors and in high grade tumors. Parson W. (2002).A. In urinary bladder.. (1990). Johnston P. and Gold L. expression of MYC gene and clinical-histopathological parameters (Sardi et al. Butler M. Opin. and Klocker H. lowgrade bladder tumors (Lianes et al. However. Curr. 1689-1692. 1993).. Coggan M... and Lucier G. Steiner H.. (1993b).. Shiina et al.N... 1994). DNA damage from micronutrient deficiencies is likely to be a major cause of cancer.. p53 deletion and tumor cell proliferation as assessed by Ki67 labeling index (Sauter et al.A.F. The expression profile of such genes were then evaluated in pathologically well characterized human tumors and one gene. Too many rodent carcinogens: mitogenesis increases mutagenesis.A. 1999). In addition.. Ther. In addition. 1995...P. MYC overexpression did not correlate with tumor grade or tumor progression (Schmitz-Drager et al.. our laboratory has used lineage related human bladder cancer cell lines.L. Genetic risk and carcinogen exposure: a common inherited defect of the carcinogen-metabolism gene glutathione S-transferase M1 (GSTM1) that increases susceptibility to bladder cancer. In addition.. Paulson D. has been suggested as a prognostic markers for patients with recurrent progressive bladder tumors (Novara et al. Brubaker L..F. Bell D.W. The ongoing integration of molecular biology with clinical science promises to bring all of this within our reach. Furthermore. it suppressed experimental lung metastasis while not affecting in vitro growth...H. stage.. These data were consistent with a role of chromosome 8 alterations in bladder cancer progression (Wagner et al. RhoGDI2 was identified whose expression was suppressed as a function of tumor stage and grade in human cancer.268 Molecular pathogenesis of bladder cancer of the urinary bladder (Furihata et al. Taylor J.. Thus the role of this gene in bladder cancer development or progression is at present unclear.. therapy can be tailored to the specific biology of the individual tumor.. Pharmacol. (1993a). However subsequent studies have not found statistical significant correlation between the methylation. Mutat. 1995). Science 249. Other genes Early studies in bladder cancer have indicated a strong association of low level MYC (8q. and the molecular basis for the biology of transitional cell bladder neoplasms.. Conclusion We have attempted to review the current understanding of both the molecular pathogenesis. a marker of aggressive human cancer and a promising target for therapy. The MDM2 (mouse double minute 2. p53-binding protein) gene is located at 12q13-14 and codes for a 90 Kd nuclear protein which is a negative regulator of P53. Bernstein L. 48.... and Webb G. The identification of heritable genetic mutations could possibly allow the early. identification of individuals at risk for certain tumors. as with MYC and ERBB2 not all studies have shown assessment of this gene product to be independently related to tumor progression (SchmitzDrager et al.. chromosome polysomy . 1997b).2-q12. Stephens E.. other studies have failed to link ERBB2 expression levels as an independent variable predicting disease progression (Underwood et al.A. 41. Carcinogenesis 14. between the MYC methylation pattern and clinical stage (Sardi et al. Suzuki T.A. specific. p53 protein expression. Pfister et al. patients with tumors positive for P53 staining had a significantly worse survival rate. Microsatellite alterations in human bladder cancer: detection of tumor cells in urine sediment and tumor tissue.. For those patients with neoplastic disease. From these studies it would appear that the role of ERBB2 as a diagnostic marker may outweigh its usefulness as a prognostic indicator.R. Mohler J. 1159-1164. . J.24) gains with tumor grade. 6. Taylor J.N. Bell D. References Ames B. Ames B.. and Lucier G. Stenzl A. 532-539. and Liotta L.W. 1997). 7-20. Recently. These results indicate that RhoGDI2 is a metastasis suppressor gene. 1997a).N. (2001). Cancer Inst. colony formation or in vivo tumorigenicity. 970-971. and DNA microarray technology to identify genes whose expression diminishes as a function of invasive and metastatic competence. Kadlubar F. 106-113. (1994). Ross V. the simultaneous assessment of MDM2 and P53 was found to be independent factors for both disease progression and survival (Pfister et al. When RhoGDI2 was transferred back into cells with metastatic ability that lacked its expression. (1990). Berger A. The recognition that both the individual genotype and the environment may combine for the ultimate determination of risk may allow patients to adapt their lifestyles for risk modification. Molecular mediators of interactions with extracellular matrix components in metastasis and angiogenesis. Ravery et al. a strong statistical association between MDM2 and P53 overexpression was found in addition to an association between MDM2 overexpression and low-stage.. Eur. Robertson C.. RhoGDI2 reconstitution in these cells blocked invasion in an organotypic assay and led to a reduction of in vitro motility (Gildea et al. Board P. Oncol. 1997). 1997). Other studies have indicated a high level of expression of this gene in malignant as compared to benign bladder epithelium (Underwood et al.

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